Registration Dossier

Toxicological information

Basic toxicokinetics

Currently viewing:

Administrative data

Endpoint:
basic toxicokinetics in vivo
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Acceptable, well documented publication which meets basic scientific principles.

Data source

Reference
Reference Type:
publication
Title:
Metabolism of triacetin-derived acetate in dogs
Author:
Bleiberg, B.
Year:
1993
Bibliographic source:
Am J Clin Nutr 58:908-11.

Materials and methods

Objective of study:
toxicokinetics
Principles of method if other than guideline:
Triacetin was administered intravenously to ten mongrel dogs 2 weeks after surgical placement of blood-sampling catheters in the aorta and in the portal, hepatic, renal, and femoral veins. [1-14C] Acetate was infused to allow quantification of organ uptake of acetate as well as systemic turnover and oxidation.
GLP compliance:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Name of test material (as cited in study report): Triacetin
- Analytical purity: no data
Radiolabelling:
yes
Remarks:
[1-14C] Acetate

Test animals

Species:
dog
Strain:
other: Mongrel
Sex:
not specified
Details on test animals and environmental conditions:
TEST ANIMALS
- Weight at study initiation: 23.4 ± 0.3 kg

Administration / exposure

Route of administration:
infusion
Vehicle:
water
Details on exposure:
Triacetin was administered intravenously to mongrel dogs (n=10) 2 weeks after surgical placement of blood-sampling catheters
in the aorta and in the portal, hepatic, renal, and femoral veins. A 18-gauge infusion catheter was inserted in the postcava via a lateral saphenous vein for subsequent tracer infusion. A tracer was diluted in 150 mmol NaCl/L containing 2 mmol NaHCO/L before infusion. After 3 h of tracer infusion, a 5% (v/v) aqueous solution of triacetin was infused at a rate of 47 µmol/kg/min and continued for an additional 4 h. [1-14C] acetate was infused to alow quantification of organ uptake of acetate as well as systemic turnover and oxidation.
Duration and frequency of treatment / exposure:
3 h tracer infusion
4 h infusion of aqueous triacetin solution at 47 µmol/kg bw/min
Doses / concentrations
Remarks:
Doses / Concentrations:
47 µmol/kg bw/min
No. of animals per sex per dose:
10
Control animals:
no
Details on study design:
Plasma acetate concentration and specific activity were determined by HPLC with [3H] acetate used as an internal standard.
The same procedure was used to determine the specific activity of D-beta-hydroxybutyrate.
The 14CO2 excretion rate was measured by using an ethanolamine trap.
Hematocrit values were obtained on all animals.
Details on dosing and sampling:
PHARMACOKINETIC STUDY (Absorption, distribution, excretion)
- Tissues and body fluids sampled: blood, plasma, breath
- Time and frequency of sampling: Blood samples were obtained from all five catheters at 15-min intervals over the last 30 min of the Triacetin infusion for measurement of plasma acetate concentration and specific activity. Breath samples were obtained at the same time points for determination of 14CO2 excretion rate.


Statistics:
Average values for plasma acetate concentration and specific activity, mean values for 14CO2 excretion rate for breath samples were evaluated.
Systemic acetate turnover and oxidation were determined by using steady-state formulas.

Results and discussion

Toxicokinetic / pharmacokinetic studies

Details on distribution in tissues:
Significant acetate uptake was demonstrated in all tissues (liver, 559 ± 68; intestine, 342 ± 23; hindlimb, 89 ± 7; and kidney, 330 ± 37 µmol/min).
Details on excretion:
Acetate clearance during Triacetin infusion 2.0 L/min.

Metabolite characterisation studies

Metabolites identified:
yes
Details on metabolites:
During intravenous administration in dogs, the majority of infused Triacetin undergoes intravascular hydrolysis, and the majority of the resulting acetate is oxidized. Systemic acetate turnover accounted for approximately 70% of (equivalent to 2214±95 µmol/min) Triacetin-derived acetate, assuming complete hydrolysis of the triglyceride. Approximately 80% of systemic acetate uptake was rapidly oxidized. It is apparent that the majority (85% equivalent to 1876±132 µmol/min) of acetate entering the system is directly oxidized. This is consistent with the generally accepted view that medium- and short-chain fatty acids undergo near quantitative oxidation rather than re-esterification or elongation.

Any other information on results incl. tables

Table 1. Average organ acetate uptake in dogs, postabsorptively.

 

Uptake

μmol/min

Hindlimb

89

Total skeletal muscle*

445

Intestine

342

Liver

559

Kidney

330

* Assumption: 20% of whole-body skeletal muscle is represented in the hindlimb.

Table 2. Plasma acetate concentration after steady-state conditions were achieved (µmol/L):

Plasma acetate concentration

[µmol/L]

Aorta

1180

Renal vein

935

Portal vein

817

Femoral vein

752

Hepatic vein

473




 

 
 

 

           

Applicant's summary and conclusion

Conclusions:
Interpretation of results (migrated information): low bioaccumulation potential based on study results
During intravenous administration in dogs, the majority of infused triacetin undergoes intravascular hydrolysis.